title: Novel cinnamyl hydroxyamides and 2-aminoanilides as histone deacetylase inhibitors: apoptotic induction and cytodifferentiation activity.
abstract: Four novel series of cinnamyl-containing histone deacetylase (HDAC) inhibitors 1-4 are described, containing hydroxamate (1 and 3) or 2-aminoanilide (2 and 4) derivatives. When screened against class I (maize HD1-B and human HDAC1) and class II (maize HD1-A and human HDAC4) HDACs, most hydroxamates and 2-aminoanilides displayed potent and selective inhibition toward class I enzymes. Immunoblotting analyses performed in U937 leukemia cells generally revealed high acetyl-H3 and low acetyl-α-tubulin levels. Exceptions are compounds 3 f-i, 3 m-o, and 4 k, which showed higher tubulin acetylation than SAHA. In U937 cells, cell-cycle blockade in either the G₂/M or G₁/S phase was observed with 1-4. Five hydroxamates (compounds 1 h-l) effected a two- to greater than threefold greater percent apoptosis than SAHA, and in the CD11c cytodifferentiation test some 2-aminoanilides belonging to both series 2 and 4 were more active than MS-275. The highest-scoring derivatives in terms of apoptosis (1 k, 1 l) or cytodifferentiation (2 c, 4 n) also showed antiproliferative activity in U937 cells, thus representing valuable tools for study in other cancer contexts.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma "La Sapienza", P.le A. Moro 5, 00185 Roma, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Valente
authors.forename: Maria
authors.initials: M
authors.lastname: Tardugno
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Conte
authors.forename: Roberto
authors.initials: R
authors.lastname: Cirilli
authors.forename: Andrea
authors.initials: A
authors.lastname: Perrone
authors.forename: Rino
authors.initials: R
authors.lastname: Ragno
authors.forename: Silvia
authors.initials: S
authors.lastname: Simeoni
authors.forename: Anna
authors.initials: A
authors.lastname: Tramontano
authors.forename: Silvio
authors.initials: S
authors.lastname: Massa
authors.forename: Angela
authors.initials: A
authors.lastname: Nebbioso
authors.forename: Marco
authors.initials: M
authors.lastname: Miceli
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Franci
authors.forename: Gerald
authors.initials: G
authors.lastname: Brosch
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002934:Cinnamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006900:Hydroxylation; D015151:Immunoblotting; D011437:Propylamines / Q000737:chemistry; D013329:Structure-Activity Relationship; D020298:U937 Cells
chemical_list: D000577:Amides; D000813:Anilides; D000970:Antineoplastic Agents; D002934:Cinnamates; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011437:Propylamines; C058556:cinnamylamine